The cephalosporin antibiotic art has developed over the past quarter century from Cephalosporin C and its nucleus, 7-aminocephalosporanic acid (7-ACA) to a great number of useful cephalosporin antibiotic compounds having a variety of substituent groups, mostly at the 3- and 7-positions of the 3-cephem ring system nucleus thereof. See the Journal of the American Chemical Society, (1962), 84, p. 3400 for the introduction of the "cepham" and "cephem" ring system nomenclature, now common in patents and literature in this art.
The early work in replacement of the 3-acetoxy group from Cephalosporin C, 7-ACA or other 3-acetoxymethyl-.DELTA..sup.3 -cephem cephalosporin starting materials is well documented. For example, see "The Chemistry of Cephalosporins. IV. Acetoxyl Replacements with Xanthates and Dithiocarbames" by E. Van Heyningen, et al. in Journal of Medicinal Chemistry, 8, March, 1965, pp. 174-181; "Cephalosporanic Acids. Part III. Reactions with Pyridine - Kinetics and Mechanism" by A. B. Taylor in Journal of the Chemical Society (London), 1965, Part V, pp. 7020-7029; and "Cephalosporanic Acids. Part II. Displacement of the Acetoxy Group by Nucleophiles" by J. D. Cocker, et al. in Journal of the Chemical Society (London), 1965, Part IV, pp. 5015-5031.
More recently, efforts have been directed to studies of processes for preparing various cephalosporin compounds starting from 3-hydroxymethyl-.DELTA..sup.3 -cephem 4-carboxylic acid compounds such as desacetylcephalosporin C. For example, Glaxo U.S. Pat. No. 3,948,906 describes preparation of monochloro-, dichloro and trichloroacetoxy groups on the 3-methyl carbon of the .DELTA..sup.3 -cephalosporin by conversion of a 3-hydroxymethyl-7-protected amino-.DELTA..sup.3 -cephem-4-carboxylic acid to a respective 4-carboxylic acid ester intermediate, which is then reacted at the 3-hydroxymethyl-position to form the respective 3-chlorinated acetoxy-methyl group, which reaction is then followed by a 4-de-esterification or de-protection step. However, such 3-activated estermethyl process has the disadvantage of being multi-step. More direct methods would be desirable. Unfortunately, prior processes which do not protect the .DELTA..sup.3 -cephalosporin-4-carboxylic acid group are well known to produce substantial yield lowering quantities of the competing, undesired lactone by-product and/or by-products arising from .DELTA..sup.3 .fwdarw. .DELTA..sup.2 double bond isomerization. The acid protecting group must be carefully chosen such that this .DELTA..sup.3 .fwdarw..DELTA..sup.2 isomerization does not occur during protection or deprotection. See also "A New Route to Semisynthetic Cephalosporins from Desacetylcephalosporin C. I. Synthesis of 3-Heterocyclicthiomethyl-cephalosporins" by S. Tsushima, et al. in Chem. Pharm. Bull. (Japan-in English), 27(3), pp. 696-702 (1979) disclosing the preparation of the 3-acetoacetoxymethyl-.DELTA..sup.3 -cephem-4-carboxylic acid intermediate from the 3-hydroxymethyl-starting material, and Tsushima, et al., U.S. Pat. No. 4,323,676 which claims the process for preparing 3-acyloxymethyl-cephem compounds, with some defined carboxylic acid anhydrides. More importantly, this '676 patent sets forth in columns 1 and 2 thereof the prior problems which occurred in attempts to start with and process 3-hydroxymethyl-4-carboxy-.DELTA..sup.3 -cephem acids to desired 3-nucleophile-methyl cephalosporin antibiotic end products. Yield lowering lactone formation occurred or there was a need to protect and later de-protect the 4-carboxyl group in reactions on the 3-hydroxyl methyl group of the starting material.
However, the 3-acetoacetoxymethyl group on the resulting cephalosporin intermediate compounds of the '676 patent are limited in their further utilities. It is well known that the more acidic the leaving group on the 3-hydroxymethyl group is, the more readily it is displaced by nucleophiles. Therefore, any ester whose corresponding acid is more acidic than acetic acid (pKa 4.75) will be a better leaving group than acetate, and, in particular, groups having a pKa of less than 4.0 are preferred. See the discussion in U.S. Pat. No. 3,948,906, top of column 2 and middle of column 3. The acetoacetic acid from the acetoacetyl group taught by the above Tsushima U.S. Pat. No. 9,323,676 has a pKa of about 3.6. Groups more acid are more preferable because they may be displaced more readily, e.g., under milder process conditions. Those in the cephalosporin chemical process arts continue to study to find process routes for the preparation in high yields of 3-(activated ester)-methyl-cephalosporin intermediate compounds having wider intermediate utility from 3-hydroxymethyl-3-cephem-4-carboxylic starting compounds, in overall processes for making a wide range of desirable 3-nucleophile-methyl cephalosporin antibiotic end products.